Second-generation antipsychotic medications have proven quite effective in reducing symptoms of schizophrenia, but little progress has been made in improving behavioral outcomes of relevance to affected individuals, their families, and policymakers. A major goal of research on functional outcomes in schizophrenia should be to understand for whom and under what circumstances interventions aimed at improving functional abilities are effective. Currently, research on the assessment or improvement of functional outcomes is usually conducted in a primarily psychosocial context, while genetic studies are typically viewed as conceptually quite distant from such studies. However, it is highly likely that there are significant direct and/or indirect genetic influences on functional outcomes such as interpersonal skills, participation in community activities, and work skills. In this proposal, we seek to bridge these two seemingly distant ends of the spectrum of schizophrenia research. Our previous non-genetic research showed that cognitive functions and negative symptoms influence functional capacity, which in turn influences functional outcomes in schizophrenia. On the other hand, depressive symptoms independently predicted functional outcomes. Separate work by our group and others has demonstrated the heritability of many cognitive abilities and symptoms, and some progress has been made in identifying specific genes that influence some of these traits. We now propose to test the hypothesis that several specific genes will contribute to functional outcomes either through direct pathways or through their influences on cognition and symptoms. To accomplish this goal, we are proposing the following specific aims: 1) To determine which specific neuropsychological functions and symptom dimensions predict functional capacity and functional outcomes in schizophrenia; 2) To detect direct and mediated effects of genetic polymorphisms on real-world functioning, specifically focusing on: a) empirically supported candidate polymorphisms; b) all haplotype-tagging single nucleotide polymorphisms in and around empirically supported candidate genes; and c) ontologically related candidate genes; and 3) To establish multivariate models of functional outcomes, by: a) evaluating possible additive and epistatic interactions between candidate genes; and b) evaluating pleiotropic effects of each candidate gene. Linking basic research with the study of functional performance is only a first step toward future development of novel therapeutics targeted at aberrant proteins, but it is an important one. The development of such treatments is likely to be a long-term process, but one that could ultimately enhance psychosocial interventions to improve real-world functioning. PUBLIC HEALTH RELEVANCE: We will test the hypothesis that several specific genes contribute to functional outcomes, either through direct pathways or through their influences on cognition and symptoms, in schizophrenic patients. This project has important implications for personalized treatment and case management. By linking basic genetic research with the study of functional performance, we take the first step toward the development of new types of treatments targeting aberrant proteins, which could ultimately enhance psychosocial interventions and lead to an improvement in real-world functioning. [unreadable] [unreadable] [unreadable]